Phenylazole compound, production process therefor and antioxidant

ABSTRACT

The present invention relates to a compound represented by formula (1):  
                 
 
(wherein R represents a hydrogen atom or a C 1-6  alkyl group which may be substituted, A represents an imidazolyl group or a pyrazolyl group, B represents a group represented by the following formula:  
                 
 
(wherein R5 and R6 each independently represents a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a C 1-6  alkyl group, a C 1-6  alkoxy group, or the like, k represents 0 or an integer of 1 to 15, and R5 and R6 may be identical or different from each other, when k is 2 or more), and Z represents a substituted chroman-2-yl group, a substituted 2,3-dihydrobenzofuran-2-yl, a substituted thiochroman-2-yl group, a substituted 2,3-dihydrobenzothiophene-2-yl group, or a substituted 1,3-benzoxathiol-2-yl group).

TECHNICAL FIELD

The present invention relates to a novel phenylazole compound, aproduction process therefor, an antioxidant having the compound as itsactive ingredient, and a kidney disease treatment agent, cerebrovasculardisease treatment agent, retinal oxidation disorder inhibitor,lipoxygenase inhibitor, and 20-HETE synthase inhibitor, that uses theantioxidant.

BACKGROUND ART

The formation of lipid peroxides in the body and their associatedradical reactions have recently been demonstrated to have variousdetrimental effects on the body resulting from membrane damage,cytotoxicity and so forth. Accompanying this finding, various attemptshave been made to apply antioxidants and lipid peroxide formationinhibitors to pharmaceuticals, and research has been conducted onnumerous types of antioxidants (see, for example, Non-Patent Literature1). Known examples of these antioxidants include pharmaceuticalcompositions used for the treatment and prevention of endotoxin shocktriggered by inflammation or infection that contain a specific quinonederivative (see, for example, Patent Literature 1), hydroxamic acidderivatives used for the treatment and prevention of autoimmune diseaseshaving cell growth inhibitory action and vascularization inhibitoryaction (see, for example, Patent Literature 2), and2,3-dihydrobenzofuran derivatives that are useful as antioxidants andradical scavengers (see, for example, Patent Literatures 3, 4 and 5). Inaddition, other known examples include imidazole-based compounds havinganti-hyperlipemia action that are useful for the treatment andprevention of arteriosclerosis (see, for example, Patent Literature 6),and benzothiazine carboxamides represented by the following formulahaving anti-arthritis activity (see, for example, Patent Literature 7).

Moreover, other known examples include carbonyl aminophenyl imidazolederivatives (see, for example, Patent Literature 8, Patent Literature 9,and Patent Literature 10), aminodihydrobenzofuran derivatives havinglipid peroxide formation inhibitory action that are useful as preventiveand treatment agents of various diseases such as arteriosclerosis, liverdisease and cerebrovascular disorders (see, for example, PatentLiterature 11), anti-hyperlipemia drugs containing phenylazole compounds(see, for example, Patent Literature 12), dihydrobenzofuran derivativesthat significantly improve damage caused by lipids, proteins,carbohydrates and DNA occurring as a result of oxidative stress thatoccurs when antioxidation defense systems are inadequate (see, forexample, Patent Literature 13), and optically activeaminodihydrobenzofuran derivatives that are effective for improving,treating and preventing impairment of brain function accompanyingcerebral stroke or head injury (see, for example, Patent Literature 14).

Since the brain is dependent on circulating blood for its supply ofenergy despite it having a large energy demand, it is extremelysusceptible to ischemia. When the brain falls into a state of cerebralischemia as a result of having its blood flow cut off for variousreasons, active oxygen species are formed triggered by mitochondrialdamage and elevated calcium levels within nerve cells. In addition,oxygen radicals are known to be formed in extremely large amounts whenblood flow is resumed following ischemia. These active oxygen speciesultimately act on lipids, proteins, nucleic acids, or the like, which issaid to result in their oxidation and cell death. Antioxidants are usedto treat such a condition, and in Japan, Edaravone has been approved asa brain protective drug and is used for that purpose.

Lipoxygenase (abbreviated as LO), which adds oxygen to unsaturated fattyacids such as arachidonic acid, is known to exist in the form of 5-LO,8-LO, 12-LO and 15-LO according to the site where oxygen is added. Amongthese, 5-LO is the initial enzyme in the synthesis of leucotrienes,which are potent inflammation mediators. Leucotrienes are involved invarious inflammatory diseases such as asthma, rheumatoid arthritis,inflammatory colitis and psoriasis, and their control is useful for thetreatment of these diseases. 12-LO and 15-LO react with linoleic acid,cholesterol esters, phospholipids and low-density lipoproteins(hereinafter, abbreviated as LDL) in addition to arachidonic acid, andare known to add oxygen to their unsaturated fatty acids (see Non-PatentLiterature 2). Macrophages become foamy cells by unlimited uptake ofoxidative-modified LDL by means of scavenger receptors, and this iswidely known to be the initial step in the formation of arterioscleroticfoci. 12-LO and 15-LO are represented by high levels in macrophages, andhave been clearly demonstrated to be essential as the trigger foroxidative modification of LDL (see Non-Patent Literature 3). Theircontrol is useful for the treatment of various types of diseases causedby arteriosclerosis (see Patent Literature 15).

20-Hydroxyeicosatetraenoic acid (abbreviated as “20-HETE” hereinafter)is produced by 20-HETE synthase from arachidonic acid, which is a fattyacid precursor separated from phospholipids of the cell membrane.20-HETE is known to cause dilation and constriction of themicrovasculature in major organs such as the kidneys and cerebrovascularsystem, and to promote cellular proliferation. 20-HETE is involved inmajor physiologic functions within the body, suggesting its significantparticipation in pathological states in renal disease, cerebrovasculardisease, cardiovascular disease, or the like (Non-Patent Literatures 4to 6).

Further, phenylazole derivatives (Patent Literatures 16, 17, and 18)have been reported to have an inhibitory effect on 20-HETE synthase.

Oxidative stress involving free radicals and active oxygen is thought tobe one of the causative factors of many eye diseases such as cataractand macular degeneration that frequently occurs with aging (see, forexample, Non-Patent Literatures 7 to 9). Among tissues of the eye, theretina along with the lens are known to be tissues that are susceptibleto the effects of aging (see, for example, Non-Patent Literature 10).The retina is susceptible to the effects of various free radicalsbecause it contains a large amount of higher unsaturated fatty acids andbecause it is provided with nutrients from both retinal blood vesselsand choroid blood vessels and consumes a large amount of oxygen. Forexample, light such as sunlight that enters the eyes during the entirecourse of a person's life is a typical example of oxidative stress thataffects the retina. The majority of the sunlight that reaches the earthconsists of visible light and infrared right, while ultraviolet lightthat only accounts for several percent of that light has a significanteffect on health by powerfully interacting with the body as comparedwith visible light and infrared light. Ultraviolet light is divided intoUV-A (320 to 400 nm), UV-B (280 to 320 nm) and UV-C (190 to 280 nm)according to differences in its wavelength, and although its action andstrength relative to the body differ, ultraviolet light of 290 nm orless which exhibits particularly strong cytotoxicity has conventionallybeen thought to hardly reach the earth's surface at all as a result ofbeing absorbed by the ozone layer of the stratosphere. In recent years,however, the amount of ultraviolet light that reaches the earth hasincreased due to the appearance of ozone holes thought to be caused bydestruction of the environment, and judging from rapid increases in theoccurrences of skin disorders and skin cancer related to ultravioletlight in the southern hemisphere, retinopathy is expected toconsiderably increase due to the effects of UV-A reaching the earth'ssurface.

Among various eye diseases, age-related macular degeneration is a typeof retinopathy associated with a high degree of vision loss. In the US,roughly 10 million people have mild symptoms of this disease, and morethan 450,000 have impaired vision brought on by this disorder (see, forexample, Non-Patent Literature 11). There is concern over an increasedincidence of this disease in Japan as well where the number of elderlyin the general population is increasing rapidly. Although there are manyaspects of the mechanism of occurrence of macular degeneration that arenot fully understood, the progression of this lesion has been pointedout to involve a peroxidation reaction caused by light absorption in theretina (see, for example, Non-Patent Literatures 12 and 13). Inaddition, the appearance of a lipofuscin-like fluorescent substanceknown as Druse has been observed in the early stages of its onset. Sincelipofuscin is formed from the bonding of protein and aldehyde, which isa secondary decomposition product of lipid peroxides, there is thepossibility that a lipid peroxidation reaction in the retina caused byultraviolet light or visible light may induce this type of retinopathy.

Retina disease treatment agents containing a specific dihydrofuranderivative (see, for example, Patent Literature 19), and drugs forvisual acuity and retinal changes, including macular changes of theretina, that contain propionyl L-carnitine or its pharmaceuticallyacceptable salts, and carotenoids (see, for example, Patent Literature20), are known to be useful for the prevention and treatment of theseretina diseases due to their antioxidative action.

Patent Literature 1: Japanese Unexamined Patent Application, FirstPublication No. S61-44840

Patent Literature 2: Japanese Unexamined Patent Application, FirstPublication No. H1-104033

Patent Literature 3: Japanese Unexamined Patent Application, FirstPublication No. H2-121975

Patent Literature 4: European Patent Application, Publication No. EU345593

Patent Literature 5: European Patent Application, Publication No. EU483772

Patent Literature 6: International Publication No. WO 95/29163

Patent Literature 7: German Patent Application, Publication No. DE3,407,505

Patent Literature 8: Japanese Unexamined Patent Application, FirstPublication No. S55-69567

Patent Literature 9: European Patent Application No. EU

Patent Literature 10: European Patent Application, Publication No. EU458037

Patent Literature 11: Japanese Unexamined Patent Application, FirstPublication No. H5-140142

Patent Literature 12: International Publication No. WO 00/006550

Patent Literature 13: International Publication No. WO 96/28437

Patent Literature 14: Japanese Unexamined Patent Application, FirstPublication No. H6-228136

Patent Literature 15: Japanese Unexamined Patent Application, FirstPublication No. H2-76869

Patent Literature 16: International Publication No. WO 00/0168610

Patent Literature 17: Japanese Unexamined Patent Application, FirstPublication No. 2004-010513

Patent Literature 18: International Publication No. WO 03/022821

Patent Literature 19: Japanese Unexamined Patent Application, FirstPublication No. H6-287139

Patent Literature 20 International Publication No. WO 00/07581

Non-Patent Literature 1: Biochem. Biophys. Acta, 1304, 652, 1996; J.Amer. Oil Chemists Soc., 51, 200, 1974.

Non-Patent Literature 2: Biochem. Biophys. Acta, 1304, 652, 1996.

Non-Patent Literature 3: J. Clin. Invest., 103, 15972, 1999.

Non-Patent Literature 4: J. Vascular Research, 32, 79, 1995

Non-Patent Literature 5: Am. J. Phsiol., 277, 607, 1999

Non-Patent Literature 6: Physiol. Rev., 82, 131, 2002

Non-Patent Literature 7: Anderson R. E., Kretzer F. L., Rapp L. M.:“Free Radicals and Eye Diseases”, Adv. Exp. Med. Biol., 366, 73, 1994.

Non-Patent Literature 8: Nishigori H., Lee J. W., Yamauchi Y., IwatsuruM.: “Lipid Peroxide Changes in Glucorticoid-Induced Cataract inGerminated Chicken Embryos and Effects of Ascorbic Acid”, Curr. EyeRes., 5, 37, 1986.

Non-Patent Literature 9: Truscott R. J. W., Augusteyn R. C.: “Action ofMercapto Groups in the Normal and Cataract Human Lens”, Exp. Eye Res.,25, 139, 1977.

Non-Patent Literature 10: Hiramitsu T., Armstrong D.: “PreventiveEffects of Antioxidants Against Lipid Peroxidation Reactions in theRetina”, Ophthalmic Research, 23, 196, 1991.

Non-Patent Literature 11: Vitamin Information Center (Tokyo), VICNewsletter, 105, 4, 2002.

Non-Patent Literature 12: Sachimura S.: “Cataract and Active Oxygen FreeRadicals, Active Oxygen Free Radicals”, 3, 402, 1992.

Non-Patent Literature 13: Solbach U., Keilhauer C., Knabben H., Wolf S.:“Retina Autofluorescent Images in Age-Related Macular Degeneration”,Retina, 17, 385, 1997.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide an antioxidant that iseffective for the treatment of arteriosclerosis and other ischemic organdisorders such as myocardial infarction and cerebral stroke or for thetreatment of diseases caused by oxidative cytotoxicity, and particularlyto provide an oxidation disorder inhibitor for the retina that inhibitsretinopathy caused by oxidation, and photooxidation in particular, alipoxygenase inhibitor, and a 20-HETE synthase inhibitor.

As a result of conducting extensive studies to solve the aforementionedproblems, the inventors of the present invention determined that thecause of the inadequate effectiveness of existing antioxidants is thatthe drug either does not reach the target site or ends up losingactivity before reaching the target site, and as a result of conductingextensive studies for the purpose of developing an antioxidant that hasbetter organ migration and passes easily through the blood-brain barrieror blood-retina barrier in particular, found that a compound representedby formula (1) achieves the desired effect, and that it has superior invivo antioxidative action regardless of the administration route,thereby leading to completion of the present invention.

Moreover, the inventors of the present invention also studied effects onthe retina by subjecting rat eyes to spot irradiation with a fixeddosage of UV-A. A lipofuscin-like fluorescent substance is frequentlydetected from the reaction product of proteins and aldehydes originatingin lipid peroxides during the early stages of onset of retina diseaseshaving a high degree of vision loss such as macular degeneration. Anincrease in protein in the vicinity of 66 kDa is observed that is highlyproportional to changes in eye retina tissue irradiated with UV-A, andthis protein has been observed to be an albumin-like substance based onthe results of instrument analyses and studies using albumin-free rats.Since significant increases in a lipofuscin-like fluorescent substancehave been observed due to the presence of albumin in automated oxidationreactions of retina tissue in vitro, there is a high probability thatabnormal increases in some proteins in retina tissue caused by UV-Airradiation are related to increases in fluorescent substances in theretina, and that this triggers retinopathy. The inventors of the presentinvention have previously conducted studies on retinopathy inhibitors byusing changes in this retina protein as the first biochemical indicator.During the course of those studies, the compound according to thepresent invention having strong antioxidative action was observed tomigrate to the retina in a short period of time following oraladministration, and significantly inhibited increases in the 66 kDaprotein caused by UV-A spot irradiation. After obtaining findings thatthe compound according to the present invention is effective againstretinopathy caused by oxidation, and particularly effective indiminishing the progress and symptoms of age-related maculardegeneration of the retina that increases with age, this result led tocompletion of the present invention on the basis of those findings.

Namely, the present invention is characterized by the following.1. A compound represented by formula (1):

(wherein,

-   -   R1 represents a hydrogen atom or a C₁₋₆ alkyl group which may be        substituted,    -   A represents an imidazolyl group or a pyrazolyl group        represented by the following formulae:        (wherein    -   R2 and R3 represent a hydrogen atom or a C₁₋₆ alkyl group which        may be substituted by G1,    -   R4 represents a hydrogen atom or a C₁₋₆ alkyl group which may be        substituted by G1, a C₁₋₆ alkylcarbonyl group which may be        substituted by G1, or a benzoyl group which may be substituted        by G1,    -   n represents 0 or an integer of 1 to 3,    -   p represents 0 or an integer of 1 or 2, and    -   R2 and R3 may be identical to each other, or different from each        other, when n and p are 2 or more),    -   B represents a group represented by the following formula:        (wherein    -   R5 and R6 each independently represents a hydrogen atom, a cyano        group, a hydroxyl group, a halogen atom, a C₁₋₆ alkyl group, a        C₁₋₆ alkoxy group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a        C₂₋₆ alkenyloxy group, a C₂₋₆ alkynloxy group, a C₁₋₆ acyloxy        group, or a C₃₋₆ cycloalkyl group, or a phenyl group which may        have a substituent,    -   k represents 0 or an integer of 1 to 15, and    -   R5 and R6 may be identical to each other, or different from each        other, when k is 2 or more),    -   Z represents a chroman-2-yl group which is substituted by G2, a        2,3-dihydrobenzofuran-2-yl group which is substituted by G2, a        thiochroman-2-yl group which is substituted by G2, a        2,3-dihydrobenzothiophene-2-yl group which is substituted by G2,        or a 1,3-benzoxathiol-2-yl group which is substituted by G2,    -   G1 represents a cyano group, a formyl group, a hydroxyl group,        an amino group, a dimethylamino group, or a halogen atom, and    -   G2 is represented by the following formula: NHR (wherein R        represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, or a        benzoyl group which may have a substituent) or a        pharmaceutically acceptable salt thereof.        2. A compound or pharmaceutically acceptable salt as described        in 1, wherein z is a group represented by the following formula        (A), (B) or (C):        (wherein    -   * represents an asymmetric carbon atom,    -   X1 represents an oxygen atom or a sulfur atom,    -   R7 to R17 each independently represents a hydrogen atom or a        C₁₋₆ alkyl group, and    -   G2 is represented by the following formula: NHR (wherein R        represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, or a        benzoyl group which may have a substituent)).        3. A compound or pharmaceutically acceptable salt as described        in 1 or 2, wherein A is 1-imidazolyl or 1-H-pyrazole-5-yl which        is substituted at the fourth position on the benzene ring.        4. A production process of a compound represented by formula        (1):        (wherein,    -   R1 represents a hydrogen atom or a C₁₋₆ alkyl group which may be        substituted,    -   A represents an imidazolyl group or a pyrazolyl group        represented by the following formulae:        (wherein    -   R2 and R3 represent a hydrogen atom or a C₁₋₆ alkyl group which        may be substituted by G1,    -   R4 represents a hydrogen atom or a C₁₋₆ alkyl group which may be        substituted by G1, a C₁₋₆ alkylcarbonyl group which may be        substituted by G1, or a benzoyl group which may be substituted        by G1,    -   n represents 0 or an integer of 1 to 3,    -   p represents 0 or an integer of 1 or 2, and    -   R2 and R3 may be identical to each other, or different from each        other, when n and p are 2 or more),    -   B represents a group represented by the following formula:        (wherein    -   R5 and R6 each independently represents a hydrogen atom, a cyano        group, a hydroxyl group, a halogen atom, a C₁₋₆ alkyl group, a        C₁₋₆ alkoxy group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a        C₂₋₆ alkenyloxy group, a C₂₋₆ alkynloxy group, a C₁₋₆ acyloxy        group, or a C₃₋₆ cycloalkyl group, or a phenyl group which may        have a substituent,    -   k represents 0 or an integer of 1 to 15, and    -   R5 and R6 may be identical to each other, or different from each        other, when k is 2 or more),    -   Z represents a chroman-2-yl group which is substituted by G2, a        2,3-dihydrobenzofuran-2-yl group which is substituted by G2, a        thiochroman-2-yl group which is substituted by G2, a        2,3-dihydrobenzothiophene-2-yl group which is substituted by G2,        or a 1,3-benzoxathiol-2-yl group which is substituted by G2,    -   G1 represents a cyano group, a formyl group, a hydroxyl group,        an amino group, a dimethylamino group, or a halogen atom, and    -   G2 is represented by the following formula: NHR (wherein R        represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, or a        benzoyl group which may have a substituent), including:

a step 1 in which a compound represented by the following formula (1′)

(wherein

R1 represents a hydrogen atom or a C₁₋₆ alkyl group which may besubstituted,

-   -   A represents an imidazolyl group or a pyrazolyl group        represented by the following formulae:        (wherein    -   R2 and R3 represent a hydrogen atom or a C₁₋₆ alkyl group which        may be substituted by G1,    -   R4 represents a hydrogen atom or a C₁₋₆ alkyl group which may be        substituted by G1, a C₁₋₆ alkylcarbonyl group which may be        substituted by G1, or a benzoyl group which may be substituted        by G1,    -   n represents 0 or an integer of 1 to 3,    -   p represents 0 or an integer of 1 or 2, and    -   R2 and R3 may be identical to each other, or different from each        other, when n and p are 2 or more)),    -   B represents a group represented by the following formula:        (wherein    -   R5 and R6 each independently represents a hydrogen atom, a cyano        group, a hydroxyl group, a halogen atom, a C₁₋₆ alkyl group, a        C₁₋₆ alkoxy group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a        C₂₋₆ alkenyloxy group, a C₂₋₆ alkynloxy group, a C₁₋₆ acyloxy        group, or a C₃₋₆ cycloalkyl group, or a phenyl group which may        have a substituent,    -   k represents 0 or an integer of 1 to 15, and    -   R5 and R6 may be identical to each other, or different from each        other, when k is 2 or more) and    -   Z′ is represented by the following formula (A)′, (B)′, or (C)′:        (wherein    -   * represents an asymmetric carbon atom,    -   X1 represents an oxygen atom or a sulfur atom,    -   R7 to R17 each independently represents a hydrogen atom or a        C₁₋₆ alkyl group, and    -   G2 is represented by the following formula: NHR        (wherein R represents a hydrogen atom, a C₁₋₆ alkylcarbonyl        group, or a benzoyl group which may have a substituent))        is produced by reacting an amine compound represented by formula        (2):        (wherein    -   R1 represents a hydrogen atom or a C₁₋₆ alkyl group which may be        substituted, and    -   A represents an imidazolyl group or a pyrazolyl group        represented by the following formulae:        (wherein    -   R2 and R3 represent a hydrogen atom or a C₁₋₆ alkyl group which        may be substituted by G1,    -   R4 represents a hydrogen atom or a C₁₋₆ alkyl group which may be        substituted by G1, a C₁₋₆ alkylcarbonyl group which may be        substituted by G1, or a benzoyl group which may be substituted        by G1,    -   n represents 0 or an integer of 1 to 3,    -   p represents 0 or an integer of 1 or 2, and    -   R2 and R3 may be identical to each other, or different from each        other, when n and p are 2 or more)) with a compound represented        by the following formula (3):        YOC-B-Z′  (3)        (wherein    -   Y represents a hydroxyl group or a halogen atom,    -   B represents a group represented by the following formula:        (wherein    -   R5 and R6 each independently represents a hydrogen atom, a cyano        group, a hydroxyl group, a halogen atom, a C₁₋₆ alkyl group, a        C₁₋₆ alkoxy group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a        C₂₋₆ alkenyloxy group, a C₂₋₆ alkynloxy group, a C₁₋₆ acyloxy        group, or a C₃₋₆ cycloalkyl group, or a phenyl group which may        have a substituent,    -   k represents 0 or an integer of 1 to 15, and    -   R5 and R6 may be identical to each other, or different from each        other, when k is 2 or more), and    -   Z′ is represented by the following formula (A)′, (B)′, or (C)′:        (wherein    -   * represents an asymmetric carbon atom,    -   X1 represents an oxygen atom or a sulfur atom,    -   R7 to R17 each independently represents a hydrogen atom or a        C₁₋₆ alkyl group, and    -   G2 is represented by the following formula: NHR (wherein R        represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, or a        benzoyl group which may have a substituent)); and    -   a step 2 in which the nitro compound produced in the step 1 is        converted to an amino group using a reducing agent.        5. An antioxidant that contains as its active ingredient at        least one compound represented by formula (1):        (wherein

R1 represents a hydrogen atom or a C₁₋₆ alkyl group which may besubstituted,

-   -   A represents an imidazolyl group or a pyrazolyl group        represented by the following formulae:        (wherein    -   R2 and R3 represent a hydrogen atom or a C₁₋₆ alkyl group which        may be substituted by G1,    -   R4 represents a hydrogen atom or a C₁₋₆ alkyl group which may be        substituted by G1, a C₁₋₆ alkylcarbonyl group which may be        substituted by G1, or a benzoyl group which may be substituted        by G1,    -   n represents 0 or an integer of 1 to 3,    -   p represents 0 or an integer of 1 or 2, and    -   R2 and R3 may be identical to each other, or different from each        other, when n and p are 2 or more)),    -   B represents a group represented by the following formula:        (wherein    -   R5 and R6 each independently represents a hydrogen atom, a cyano        group, a hydroxyl group, a halogen atom, a C₁₋₆ alkyl group, a        C₁₋₆ alkoxy group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a        C₂₋₆ alkenyloxy group, a C₂₋₆ alkynloxy group, a C₁₋₆ acyloxy        group, or a C₃₋₆ cycloalkyl group, or a phenyl group which may        have a substituent,    -   k represents 0 or an integer of 1 to 15, and    -   R5 and R6 may be identical to each other, or different from each        other, when k is 2 or more),    -   Z represents a chroman-2-yl group which is substituted by G2, a        2,3-dihydrobenzofuran-2-yl group which is substituted by G2, a        thiochroman-2-yl group which is substituted by G2, a        2,3-dihydrobenzothiophene-2-yl group which is substituted by G2,        or a 1,3-benzoxathiol-2-yl group which is substituted by G2,    -   G1 represents a cyano group, a formyl group, a hydroxyl group,        an amino group, a dimethylamino group, or a halogen atom, and    -   G2 is represented by the following formula: NHR (wherein R        represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, or a        benzoyl group which may have a substituent) or a        pharmaceutically acceptable salt thereof.        6. An antioxidant as described in 5, wherein in formula (1) z is        represented by the following formula (A), (B), or (C):        (wherein    -   * represents an asymmetric carbon atom,    -   X1 represents an oxygen atom or a sulfur atom,    -   R7 to R17 each independently represents a hydrogen atom or a        C₁₋₆ alkyl group, and    -   G2 is represented by the following formula: NHR (wherein R        represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, or a        benzoyl group which may have a substituent)).        7. A kidney disease, cerebrovascular or cardiovascular disease        treatment agent characterized by containing the antioxidant as        described in 6.        8. A cerebral infarction treatment agent characterized by        containing the antioxidant as described in 6.        9. A retinal oxidation disorder inhibitor characterized by        containing the antioxidant as described in 6.        10. A retinal oxidation disorder inhibitor as described in 9 for        age-related macular degeneration or diabetic retinopathy.        11. A lipoxygenase inhibitor characterized by containing the        antioxidant as described in 6.        12. A 20-hydroxyeicosatetraenoic acid (20-HETE) synthase        inhibitor characterized by containing the antioxidant as        described in 6.

BEST MODE FOR CARRYING OUT THE INVENTION

R1 preferably represents a hydrogen atom or a C₁₋₆ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl orthe like in the compound represented by the above-mentioned formula (1).Among these, a hydrogen atom or a methyl group is preferable.

R2 and R3 which are substituents on the imidazolyl group or pyrazolylgroup in the definition of A preferably represent a hydrogen atom or aC₁₋₆ alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,s-butyl, t-butyl, or the like, that may be substituted by G1.

R4 represents a hydrogen atom; a C₁₋₆ alkyl group such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, or the like, thatmay be substituted by G1, a C₁₋₆ alkyl carbonyl group such as acetyl,propionyl, butyryl, isobutyryl, valeryl, pivaloyl or the like, that maybe substituted by G1, or a benzoyl group that may be substituted by G1.

When R4 is a hydrogen atom, the pyrazolyl group can take a tautomericstructure shown below.

Preferable examples of A include a 1-imidazolyl group, 1H-pyrazol-5-ylgroup, 1-H-pyrazol-4-yl group, 1-methylpyrazol-5-yl group,1-methylpyrazol-3-yl group, and 1-benzylpyrazol-4-yl group.

R5 and R6 in the definition of B each independently represents ahydrogen atom; a cyano group; a hydroxyl group; a halogen atom such aschlorine, fluorine, bromine, iodine, or the like; a C₁₋₆ alkyl groupsuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,t-butyl or the like; or a C₁₋₆ alkyl group (that may be substituted by ahalogen atom such as chlorine, bromine, fluorine, iodine or the like, ora C₁₋₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy or thelike); a C₁₋₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy,butoxy or the like; a C₂₋₆ alkenyl group such as ethenyl, 1-propenyl,1-methylvinyl, aryl, 1-methylaryl, 2-butenyl or the like; a C₂₋₆ alkynylgroup such as ethynyl, 1-propynyl, 2-propynyl or the like, a C₂₋₆alkenyloxy group such as ethenyloxy, 1-propenyloxy, 1-methylvinyloxy,aryloxy, 1-methylaryloxy, 2-butenyloxy or the like; a C₂₋₆ alkynyloxygroup such as ethynyloxy, 1-propynyloxy, 2-propynyloxy or the like, aC₁₋₆ acyloxy group such as an acetoxy group, propionyloxy group,butyloxy group or the like; a C₃₋₆ cycloalkyl group such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or the like; or a phenyl group thatmay have at an optional position on the benzene ring a substituent suchas a nitro group; a halogen atom such as chlorine, bromine, fluorine,iodine or the like; a C₁₋₆ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, s-butyl, t-butyl, or the like; a C₁₋₆ alkoxygroup such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or the like;or a C₁₋₆ haloalkyl group such as chloromethyl, dichloromethyl,trichloromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl,pentafluoroethyl or the like.

k represents 0 or an integer of 1 to 15. When k is 2 or more, then aplurality of R5s and R6s, respectively, may be present, and thesemultiple R5 and R6 may be identical to each other or different from eachother.

R5 and R6 in B are preferably a hydrogen atom, methyl group or phenylgroup, and k is preferably 0, 1, 2, 3, 4 or 5.

Examples of Z include the following cyclic groups: a chroman-2-yl groupthat may have a substituent, a 2,3-dihydrobenzofuran-2-yl group that mayhave a substituent, a thiochroman-2-yl group that may have asubstituent, a 2,3-dihydrobenzothiophene-2-yl group that may have asubstituent, or a 1,3-benzoxathiol-2-yl group that may have asubstituent.

Groups represented by the following various structural formulae may becited for the aforementioned Z.

In the formulae, *, X1 and q have the same meaning as disclosed above.

R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 and R17 each independentlyrepresents a hydrogen atom; or a C₁₋₆ alkyl group such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl or the like.

G1 represents a cyano group; a formyl group; a hydroxyl group; an aminogroup; a dimethylamino group; or a halogen atom such as chlorine,bromine, fluorine, iodine, or the like.

G2 is represented by the following formula: NHR (wherein, R indicates ahydrogen atom; a C₁₋₆ alkylcarbonyl group such as acetyl, propionyl,butyryl, isobutyryl, valeryl, pivaloyl or the like; or a benzoyl groupthat may have a substituent such as a nitro group; a halogen atom suchas chlorine, bromine, fluorine, iodine or the like; a C₁₋₆ alkyl groupsuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,t-butyl or the like; a C₁₋₆ alkoxy group such as methoxy, ethoxy,propoxy, isopropoxy, butoxy or the like; a C₁₋₆ haloalkyl group such aschloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl,1-fluoroethyl, 1,1-difluoroethyl, pentafluoroethyl or the like).

(Production Process for the Compounds)

The compounds represented by the above formula (1) according to thepresent invention can be produced by the following process, for example.

(In the formulae, A, B, R1 and Z′ have the same meaning as disclosedabove.)

Namely, the carboxylic acid represented by formula (3) and the aminerepresented by formula (2) are subjected to dehydrocondensation by acommon method, to obtain the amide derivative represented by formula(1), which is the compound according to the present invention.

This dehydrocondensation reaction can be carried out in the presence ofa suitable condensing agent. Examples of the condensing agent include1,3-dicyclohexylcarbodiimide,1-(3-dimethylaminopropy)-3-ethylcarbodiimide,2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, and the like.

Further, the reaction can be carried out even faster by reacting thereaction system in the presence of N-hydroxysuccinimide,1-hydroxybenzotriazole, or3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine.

The reaction solvent is not particularly limited provided that it is aninert solvent in the reaction. Examples thereof include ethers such asdiethylether, tetrahydrofuran (THF), 1,4-dioxane, and the like, aromatichydrocarbons such as benzene, toluene, xylene and the like, halogenatedhydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane andthe like, acetonitrile, dimethylformamide (abbreviated as DMFhereinafter), dimethylsulfoxide (abbreviated as DMSO hereinafter),pyridine and the like.

The reaction is carried out in the range of −15° C. to roughly theboiling point of the solvent, and preferably in the range of 0 to 80° C.

Production Process 2

As another process, the compound can also be produced according to thefollowing reaction formula.

(In the formulae, A, B, R1 and Z′ have the same meaning as describedabove.)

Namely, the carboxylic acid derivative represented by formula (3′) isreacted with a halogenating agent such as thionyl chloride, phosphoruspentachloride, oxalyl chloride or the like, to obtain the acid chloride(4). Next, the obtained acid chloride is reacted with the aminerepresented by formula (2) in an inert organic solvent and in thepresence of a base.

The reaction solvent is not particularly limited provided that it is aninert solvent in the reaction. Examples thereof include ethers such asdiethylether, THF, 1,4-dioxane, or the like, aromatic hydrocarbons suchas benzene, toluene, xylene, or the like, halogenated hydrocarbons suchas dichloromethane, chloroform, 1,2-dichloroethane or the like,acetonitrile, DMF, DMSO, pyridine or the like.

Examples of the base that may be used in the reaction include aminessuch as triethylamine, pyridine, 1,8-diazabicyclo[5,4.0]undec-7-ene(abbreviated as DBU hereinafter), and the like, and inorganic salts suchas sodium hydrogencarbonate, sodium carbonate, potassium carbonate,sodium hydroxide, and the like.

The reaction is carried out in the range of −15° C. to roughly theboiling point of the solvent, and preferably in the range of 0 to 80° C.

(In the formulae, A, B, R1, Z and Z′ have the same meaning as describedabove.)

Namely, by carrying out a hydrogen addition to the nitro compoundrepresented by formula (1′) using a catalyst, the aniline compoundrepresented by formula (1) can be obtained.

Examples of catalysts include palladium carbon, platinum dioxide, Raneynickel, and the like.

Examples of the solvent include alcohols such as methanol and ethanol,ethers such as diethyl ether, THF and 1,4-dioxane, hydrocarbons such asbenzene, toluene, xylene and cyclohexane, amides such as DMF, organicacids such as formic acid and acetic acid, esters such as ethyl acetateand mixed solvents thereof.

The reaction is carried out at 0° C. to roughly the boiling point of thesolvent, and is preferably carried out at 20° C. to 80° C.

Target compounds can be produced by carrying out conventionalpost-treatments after the end of the reaction.

The structure of the compound of the present invention is determined byIR, NMR and MS.

Furthermore, the compound represented by the aforementioned formula (1)and the raw material compounds represented by the aforementionedformulae (3) and (4) can also have several optically active substancesand tautomers. These are all included in the scope of the presentinvention.

Examples of pharmaceutically acceptable salts of the compoundrepresented by the aforementioned formula (1) include salts of inorganicacids such as hydrochloric acid, sulfuric acid, nitric acid andphosphoric acid, and salts of organic acids such as acetic acid,propionic acid, lactic acid, succinic acid, tartaric acid, citric acid,benzoic acid, salicylic acid, nicotinic acid and heptagluconic acid.These can be easily produced by ordinary chemical synthesis methods.

(Antioxidant)

Since the phenylazole compound of the present invention hasantioxidative action, it can prevent the onset and progress ofarteriosclerotic lesions by preventing oxidative degeneration of lowdensity lipoproteins (hereinafter, abbreviated as LDL), so it can beapplied to treatment agents for arteriosclerosis. Also, it is useful asa treatment agent for various diseases such as senile dementia-relateddiseases, heart disease, cancer, diabetes, gastrointestinal diseases,burns, eye diseases and kidney disease that are based on oxidativeaction. Moreover, although various types of active oxygen are generatedwhen blood is reperfused at ischemic sites, and tissue damage isexacerbated due to cell membrane damage caused by lipid peroxidation inischemic organ diseases such as cerebral stroke and myocardialinfarction, the phenylazole compound of the present invention is able toprevent tissue damage at sites of ischemic lesions by removing thevarious types of active oxygen and lipid peroxides due to itsantioxidative activity, so it can be applied to treatment agents forischemic organ disorders. In addition, since the phenylazole compound ofthe present invention has lipoxygenase inhibitory action and 20-HETEsynthase inhibitory action, it can inhibit the conversion of arachidonicacid to HPETE by inhibiting the action of lipoxygenase and theproduction of 20-HETE by inhibiting 20-HETE synthase. Moreover, some ofthe compounds according to the present invention has a lowdopamine-release inhibitory action, which results in low possibility ofcausing parkinsonian side effect or the like.

Moreover, the phenylazole compound of the present invention can be usedfor the prevention and treatment of diseases caused by oxidativedisorders of the retina, diabetes, hypertension, arteriosclerosis,anemia, leukemia, connective tissue diseases such as systemic lupuserythematosus or sclerosis, vascular disorders, inflammatory, ordegenerative lesions of the retina caused by systemic diseases such ascongenital metabolic abnormalities such as Tay-Sacks disease orVogt-Spielmeyer disease, disorders of retinal blood vessels such asretinopathy of immaturity, retinal vein occlusion, retinal arteryocclusion or retinal periphlebitis, inflammation or degeneration of theretina caused by retina detachment or injury, degenerative diseases ofthe retina accompanying aging such as age-related macular degeneration,or local retina diseases such as congenital retina degenerativediseases, and is particularly useful as a treatment agent for diseasessuch as age-related macular degeneration that occur due tophotooxidative disorders.

The antioxidant according to the present invention is not particularlylimited, provided that it contains as its active ingredient at least oneselected from the phenylazole compounds according to the presentinvention having the aforementioned antioxidative action and thepharmaceutically acceptable salts thereof, and it can be administered asa drug for the aforementioned diseases by any arbitrary route. Examplesof the administration route include oral, transnasal, parenteral, local,transcutaneous or transrectal administration. Its drug form may be asuitable drug form such as a solid, semi-solid, freeze-dried powder orliquid, specific examples of which include tablets, suppositories,pills, soft and hard capsules, powders, liquids, injection preparations,suspensions, aerosols and sustained-release preparations, which allow anaccurate dosage to be formulated and administered easily.

In addition, an antioxidant of the present invention can be in the formof a composition that contains in addition to an active ingredient andcommonly used pharmaceutical carriers or vehicles, other drugs,adjuvants and so forth within a range that does not react with otheringredients. This composition can be made to contain the activeingredient at 1 to 99% by weight and a suitable pharmaceutical carrieror vehicle at 99 to 1% by weight corresponding to the administrationroute, and preferably to contain 5 to 75% by weight of the activeingredient and a suitable pharmaceutical carrier or vehicle as theremainder.

In the antioxidant according to the present invention, a small amount ofan auxiliary substance such as a lubricant, emulsifier, pH buffer,antioxidant or the like may be contained within a range that does reactwith the other ingredients as desired regardless of the administrationroute thereof, examples of which include citric acid, sorbitanmonolaurate, triethanol amine oleate and butylated hydroxytoluene.

This type of preparation can be produced according to the conventionalmethod, for example, the description taught in Remington'sPharmaceutical Sciences, Volume 18, Mack Publishing Company, Easton,Pa., 1990.

In the antioxidant of the present invention, the therapeuticallyeffective amount of the compound represented by formula (1) or thepharmaceutically acceptable salt thereof varies according to theindividual and the symptoms of the disease being treated. Normally, thedaily therapeutically effective dosage may be 0.14 mg to 14.3 mg/day ofat least one compound represented by formula (1) or pharmaceuticallyacceptable salt thereof per 1 kg of body weight, preferably 0.7 mg to 10mg/day per 1 kg of body weight, and more preferably 1.4 mg to 7.2 mg/dayper 1 kg of body weight. For example, in the case of administering to ahuman having a body weight of 70 kg, the dosage range of the compound offormula (1) or the pharmaceutically acceptable salt thereof is 10 mg to1.0 g per day, preferably 50 mg to 700 mg per day, and more preferably100 mg to 500 mg per day. However, this dosage range is meant to serveonly as a reference, and the dosage may be made to be outside theseranges according to the symptoms being treated.

Examples of the vehicles contained in the antioxidant for oraladministration according to the present invention include any normallyused vehicles such as pharmaceutical mannitol, lactose, starch,gelatinized starch, magnesium stearate, sodium saccharine, talc,cellulose ether derivatives, glucose, gelatin, sucrose, citrates andpropyl gallate. In addition, the antioxidant for oral administration mayalso contain a diluent such as lactose, sucrose or dicalcium phosphate,a disintegration agent such as cross carmellose sodium or derivativesthereof, a binder such as magnesium stearate, or a lubricant such asstarch, gum arabic, polyvinyl pyrrolidone, gelatin or cellulose etherderivatives.

In the case of using as an injection preparation, sterile, aqueous andnon-aqueous solutions, suspensions or emulsions may be contained.Examples of diluents of aqueous solutions and suspensions includedistilled water for injection and physiological saline. Examples ofdiluents of non-aqueous solutions and suspensions include propyleneglycol, polyethylene glycol, vegetable oils such as olive oil, alcoholssuch as ethanol, and Polysorbate (trade name). This type of compositionmay also additionally contain an additive such as an isotonic agent,antiseptic, lubricant, emulsifier, dispersant, stabilizer (for example,lactose) and solubilization or solubility adjuvant. These can also beused by filtering by passing through a bacteria-retaining filter,producing a solid composition of a disinfectant, and dissolving insterile water or sterile injection solvent prior to use.

In addition, in the case of using the antioxidant of the presentinvention in the form of a suppository, a carrier that graduallydissolves in the body such as polyoxyethylene glycol or polyethyleneglycol (hereinafter, abbreviated as PEG), specific examples of whichinclude PEG1000 (96%) and PEG4000 (4%), may be used, and an example ofsuch a suppository has 0.5 to 50% by weight of the compound of formula(1) or the pharmaceutically acceptable salt thereof dispersed in thecarrier.

In the case of using the antioxidant of the present invention in theform of a liquid, water, saline solution, aqueous dextrose solution,glycerol, ethanol or the like is used as a carrier, and the liquid ispreferably in the form of a solution or suspension obtained by treatmentsuch as dissolving or dispersing 0.5 to 50% by weight of the compound offormula (1) or the pharmaceutically acceptable salt thereof along withan arbitrary pharmaceutical adjuvant in the carrier.

(Retina Photooxidative Disorder Inhibitor)

There are no particular limitations on a retina photooxidative disorderinhibitor of the present invention provided that it contains as itsactive ingredient one or more phenylazole compounds of the presentinvention and pharmaceutically acceptable salts thereof having theaforementioned antioxidative action, and the administration route,administration form and dosage can be the same as the route, form anddosage of the aforementioned antioxidant. In addition, it may alsocontain the same preparation ingredients, carriers and adjuvants, etc.as the aforementioned antioxidant, one or more types of vehicles,disintegration agents or binders, etc. as well as other retina oxidativedisorder inhibitors that do not react with the active ingredient may besuitably added, and ingredients having other pharmacological effects maybe suitably contained in addition to the aforementioned ingredients. Inaddition, the administration form can also be in the form of anophthalmic solution or ophthalmic ointment in addition to the sameadministration forms as those of the aforementioned antioxidant.

In the case of using a retina photooxidative disorder inhibitor of thepresent invention in the form of an ophthalmic solution, it can beobtained in the form of an aqueous solution or suspension by adding thephenylazole compound of the present invention to a normally used basesolvent, and adjusting the pH to 4 to 10 and preferably to 5 to 9. Theophthalmic solution is preferably subjected to sterilization treatmentto obtain a sterile product, and the sterilization treatment can becarried out at any stage of the production process. The concentration ofthe phenylazole compound of the present invention in an ophthalmicsolution is 0.001 to 3% (W/V) and preferably 0.01 to 1% (W/V), and thedosage can be several drops each one to four times per day according tothe degree of the symptoms, patient status and various other conditions.The aforementioned dosage is meant to serve only as a reference, and thedosage can also be increased beyond these ranges.

Various types of additives such as a buffer, isotonic agent, antiseptic,pH adjuster, thickener, chelating agent or solubilization agent may besuitably added to the aforementioned ophthalmic solution within a rangethat does not react with a phenylazole compound of the presentinvention. Examples of the buffers include citrate buffers, tartratebuffers, acetate buffers and amino acids. Examples of isotonic agentsinclude sugars such as sorbitol, glucose and mannitol, polyvalentalcohols such as glycerin, polyethylene glycol and propylene glycol, andsalts such as sodium chloride. Examples of antiseptics includeparaoxybenzoic acid esters such as methyl paraoxybenzoate and ethylparaoxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid andsalts thereof. Examples of pH adjusters include phosphoric acid andsodium hydroxide. Examples of thickeners include hydroxyethyl cellulose,hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose and salts thereof. Examples ofchelating agents include sodium edetate, sodium citrate and condensedsodium phosphate. Examples of solubilization agents include ethanol andpolyoxyethylene hardened castor oil.

In addition, in the case of using the retina photooxidative disorderinhibitor of the present invention in the form of an ophthalmicointment, the phenylazole compound of the present invention may be mixedwith a normally used ointment base such as purified lanolin, whiteVaseline, Macrogol, Plastibase and liquid paraffin, and it is preferablysubjected to sterilization treatment to obtain a sterile product. Theconcentration of the phenylazole compound of the present invention inthe ophthalmic ointment is normally 0.001 to 3% (W/V) and preferably0.01 to 1% (W/V), and the number of administrations may be one to fourtimes per day according to the degree of the symptoms, patient statusand various other conditions. The aforementioned number ofadministrations is meant to serve only as a reference, and the number ofadministrations can also be increased beyond these ranges.

Since a retina photooxidative disorder inhibitor of the presentinvention has superior antioxidative action, it is effective for theprevention and treatment of degenerative diseases of the retinaaccompanying aging such as age-related macular degeneration.

Although the following provides a detailed explanation of thephenylazole compound of the present invention through its examples, thetechnical scope of the present invention is not limited to theseexamples.

EXAMPLE 1 Step 1: Production of (±)-(5-nitro-2, 4, 6,7-tetramethyldihydrobenzofuran-2-yl)-N-[4-(imidazol-1-yl)phenyl]carboxamide

1.06 g of (±)-2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-carboxylicacid, 0.64 g of 1-(4-aminophenyl)imidazole, 0.85 g of1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride, 0.68 g of1-hydroxybenzotriazole, and 0.7 ml of triethylamine were added to 8 mlof DMF and stirred for 3 hours at 60° C. After cooling, the reactionmixture was poured into ice-water, and the separated product was thenextracted with chloroform. The organic layer was washed with brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform:methanol=100:3), to obtain 1.01 g of the target compound.

Step 2: Production of (±)-(5-amino-2, 4, 6,7-tetramethyldihydrobenzofuran-2-yl)-N-[4-(imidazol-1-yl)phenyl]carboxamide

1.01 g of(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-yl)-N-[4-(imidazol-1-yl)phenyl]carboxamide, 0.5 g of 10% palladium carbon, and 15 ml of methanolwere added to an autoclave and stirred overnight under a hydrogenpressure of 5 kg/cm². The reaction mixture was filtered through Celite,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform:methanol=100:3), to obtain0.33 g of the target compound. The melting point was 160 to 163° C.

REFERENCE EXAMPLE 1 Production of 2,3,5-trimethylphenyl 2-methylpropenylether

91.1 g of 2,3,5-trimethylphenol, 65.3 g of 3-chloro-2-methylpropene, and99 g of potassium carbonate were added to 700 ml of DMF, and stirred for3 hours at 80° C. After cooling, the reaction mixture was poured intoice-water, and extracted with ethyl acetate. The extract was washed withwater and brine, dried with anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (benzene:hexane=1:1), to obtain 102 g of thetarget compound.

REFERENCE EXAMPLE 2 Production of 2-aryl-3,5,6-trimethylphenol

26.6 g of 2,3,5-trimethylphenyl 2-methylpropenyl ether was dissolved in131 ml of diethylaniline, and stirred at 200° C. under an argonatmosphere for 2 hours and cooled. The reaction mixture was poured into6N-hydrochloric acid and extracted with ether. The extract was washedwith dilute hydrochloric acid, water, and brine, dried with anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (benzene:hexane=1:1),to obtain 21.4 g of the target compound.

REFERENCE EXAMPLE 3 Production of2-hydroxymethyl-2,4,6,7-tetramethyldihydrobenzofuran

To 31.86 g of 2-aryl-3,5,6-trimethylphenol which was dissolved in 600 mlof methylene chloride, 47.5 g of m-chloroperoxybenzoic acid wasgradually added at 0° C. The mixture was stirred at 0° C. for 2 hours,and poured into aqueous sodium hydrogencarbonate. The organic layer wasextracted with chloroform, washed with aqueous sodium hydrogencarbonate,dried with anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform), to obtain 17 g of the target compound.

REFERENCE EXAMPLE 4 Production of2-hydroxymethyl-2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran

To 2.3 g 2-hydroxymethyl-2,4,6,7-tetramethyldihydrobenzofuran which wasdissolved in 30 ml of acetic anhydride, 1.9 ml of nitric acid was addeddropwise at 0° C. After stirring for 1 hour at 0° C., the mixture waspoured into ice-water, and stirred at room temperature for 1 hour. Thereaction mixture was extracted with ether, washed with brine, dried withanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(chloroform), to obtain 1.34 g of the target substance.

REFERENCE EXAMPLE 5 Production of2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-aldehyde

0.57 ml of oxalyl chloride was dissolved in 12 ml of methylene chlorideunder an argon atmosphere, and cooled to −78° C. A solution of DMSO (1.1ml) in methylene chloride (2 ml) was added dropwise below −65° C., andstirred for 10 minutes. Then, a solution of2-hydroxymethyl-2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran (1.34 g) inmethylene chloride (4 ml) was added dropwise to the mixture, and stirredfor 3 hours at −78° C. After completion of the reaction, 4.2 ml oftriethylamine was added dropwise and the mixture was then warmed to roomtemperature, and 1-N hydrochloric acid was added to the mixture. Thereaction mixture was extracted with chloroform, washed with brine, driedwith anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform), to obtain 0.86 g of the target compound.

REFERENCE EXAMPLE 6 Production of2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-carboxylic acid

To a solution of 2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-aldehyde(2.39 g) and 2-methyl-2-butene (31 g) in t-butanol (190 ml), a solutionof sodium chlorite (7.77 g) and sodium dihydrogen phosphate (10.1 g) inwater (78 ml) was added dropwise under ice cooling, and stirred for 2hours at room temperature. After 2-methyl-2-butene and t-butanol weredistilled off under reduced pressure, and water was added to theresidue, the mixture was extracted with ether. The extract was washedwith brine, dried with anhydrous magnesium sulfate, and concentratedunder reduced pressure. Ether-hexane was then added to the residue, thecrystals precipitated were filtered off to obtain 1.20 g of the targetcompound.

REFERENCE EXAMPLE 7 Production of6-nitro-2-methoxymethyl-2,5,7,8-tetramethylchroman-4-one

To a solution of 5-nitro-2-hydroxy-3,4,6-trimethylacetophenone (66.5 g)and methoxyacetone (78.8 g) in toluene (500 ml), 6.4 g of pyrrolidinewas added at room temperature, stirred for 24 hours at room temperature,and refluxed for 3 hours. The reaction mixture was concentrated, and theresidue was purified by silica gel column chromatography (hexane:ethylacetate=7:1→3:1) to obtain 29.2 g of the target compound.

REFERENCE EXAMPLE 8 Production of6-nitro-4-hydroxy-2-methoxymethyl-2,5,7,8-tetramethylchroman

To a solution of6-nitro-2-methoxymethyl-2,5,7,8-tetramethylchroman-4-one (10 g) inmethanol (100 ml), sodium borohydride (1.3 g) was added at 0° C., andstirred for 1 hour at 0° C. The reaction mixture was then poured intowater, and extracted with ethyl acetate. The organic layer was washedwith brine, dried with anhydrous magnesium sulfate, and the solvent wasevaporated to obtain 10.1 g of the target compound.

REFERENCE EXAMPLE 9 Production of6-nitro-2-methoxymethyl-2,5,7,8-tetramethyl (2H) chroman

To a solution of6-nitro-4-hydroxy-2-methoxymethyl-2,5,7,8-tetramethylchroman (10.1 g) inbenzene (200 ml), p-toluene sulfonic acid (1.0 g) was added. The mixturewas refluxed using a Dean-Stark apparatus for 2 hours, poured intowater, and extracted with ethyl acetate. The organic layer was washedwith an aqueous solution of saturated sodium hydrogencarbonate, washedwith brine, and dried with anhydrous magnesium sulfate. After magnesiumsulfate was removed by filtering, the filtrate was concentrated underreduced pressure to obtain 9.4 g of the target compound in oil form.

REFERENCE EXAMPLE 10 Production of6-nitro-2-methoxymethyl-2,5,7,8-tetramethylchroman

To 9.4 g of 6-nitro-2-methoxymethyl-2,5,7,8-tetramethyl (2H) chromanwhich was dissolved in 100 ml of ethanol, 1.0 g of 10% palladiumcharcoal was added. Catalytic hydrogenation was carried out under ahydrogen pressure of 1 atm for 24 hours at room temperature. After thereaction was completed, the reaction mixture was filtered andconcentrated under reduced pressure to obtain 9.5 g of the targetcompound in oil form.

REFERENCE EXAMPLE 11 Production of6-nitro-2-hydroxymethyl-2,5,7,8-tetramethyl chroman

To 9.5 g of 6-nitro-2-methoxymethyl-2,5,7,8-tetramethyl chroman whichwas dissolved in 80 ml of methylene chloride, 31.4 ml of a 1M borontribromide solution in methylene chloride was added at 0° C. under anitrogen gas stream, and stirred for 3 hours at 0° C. After completionof the reaction, the reaction mixture was poured into water, andextracted with chloroform. The organic layer was washed with brine, anddried with anhydrous magnesium sulfate. The solvent was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1), to obtain 4.5 g of the targetcompound.

REFERENCE EXAMPLE 12 Production of 6-nitro-2-formyl-2,5,7,8-tetramethylchroman

To a solution of oxalyl chloride (1.6 ml) in methylene chloride (40 ml)at −60° C. under a nitrogen gas stream, 3.1 ml of DMSO was addeddropwise at −60° C., and stirred for 5 minutes. A solution of 3.9 g of6-nitro-2-hydroxymethyl-2, 5, 7, 8-tetramethyl chroman in 10 ml ofmethylene chloride was added dropwise under a nitrogen gas stream at−60° C., and then stirred for 30 minutes at −60° C. Next, 12 ml oftriethylamine was added at −60° C., and warmed gradually to roomtemperature to complete the reaction. After completion of the reaction,the reaction mixture was poured into water, and extracted withchloroform. The organic layer was washed with brine, and dried withanhydrous magnesium sulfate. The solvent was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=2:1), to obtain 3.4 g of the target compound incrystal form.

REFERENCE EXAMPLE 13 Production of 6-nitro-2,5,7,8-tetramethylchroman-2-carboxylic acid

To a solution of 6-nitro-2-formyl-2,5,7,8-tetramethyl chroman (2.3 g) int-butanol (150 ml), 23 g of 2-methyl-2-butene was added at roomtemperature. A solution of sodium chlorite (5.8 g) and sodium dihydrogenphosphate dihydrate (7.6 g) in water (60 ml) was added dropwise at roomtemperature, and stirred for 2 hours at room temperature. Aftercompletion of the reaction, the reaction mixture was poured into water,and extracted with ether. 5% sodium hydrogencarbonate was added to themixture, and the ether layer was discarded. The pH of the aqueous layerwas adjusted to a pH of 4 using 10% hydrochloric acid, and extractedwith ethyl acetate. The organic layer was washed with brine, and driedwith anhydrous magnesium sulfate. The solvent was concentrated underreduced pressure, and the resulting crystals were washed with hexane toobtain 1.6 g of the target compound.

The examples of the compounds according to the present invention, whichinclude those compounds disclosed in the preceding examples, are shownin Table 1. Note that the meaning of the notations and abbreviations inthe table is as follows. (& indicates that NMR data is disclosed).

Me: methyl

a1: 1-imidazolyl

a2: 1H-pyrazole-5-yl

a3: 1H-pyrazole-4-yl

a4: 1-methylpyrazole-5-yl

a5: 1-methylpyrazole-3-yl

a6: 1-benzylpyrazole-4-yl

a7: 2-methyl-1-imidazolyl

TABLE 1

Physical constant Compound [ ] melting Number A*1 B Z temp. ° C. 1 4-a1— h1 [160-163] 2 4-a1 — h2 [154-156] 3 4-a1 — h3 4 4-a1 CH₂ h1 5 4-a1CH₂ h2 6 4-a1 CH₂ h3 7 4-a1 CH₂CH₂ h1 viscous oil & NMR 8 4-a1 CH₂CH₂ h29 4-a1 CH₂CH₂ h3 10 4-a1 CH(Me)CH₂ h1 11 4-a1 CH(Me)CH₂ h2 12 4-a1CH(Me)CH₂ h3 13 3-a1 — h1 [161-165] 14 3-a1 — h2 [73-75] 15 3-a1 — h3 163-a1 CH₂ h1 17 3-a1 CH₂ h2 18 3-a1 CH₂ h3 19 3-a1 CH₂CH₂ h1 20 3-a1CH₂CH₂ h2 21 3-a1 CH₂CH₂ h3 22 3-a1 CH(Me)CH₂ h1 23 3-a1 CH(Me)CH₂ h2 243-a1 CH(Me)CH₂ h3 25 2-a1 — h1 [162-163] 26 2-a1 — h2 27 2-a1 — h3 282-a1 CH₂ h1 29 2-a1 CH₂ h2 30 2-a1 CH₂ h3 31 2-a1 CH₂CH₂ h1 32 2-a1CH₂CH₂ h2 33 2-a1 CH₂CH₂ h3 34 2-a1 CH(Me)CH₂ h1 35 2-a1 CH(Me)CH₂ h2 362-a1 CH(Me)CH₂ h3 37 4-a2 — h1 [161-164] 38 4-a2 — h2 [102-104] 39 4-a2— h3 40 4-a2 CH₂ h1 41 4-a2 CH₂ h2 42 4-a2 CH₂ h3 43 4-a2 CH₂CH₂ h1 444-a2 CH₂CH₂ h2 45 4-a2 CH₂CH₂ h3 [196-202] 46 4-a2 CH(Me)CH₂ h1 47 4-a2CH(Me)CH₂ h2 48 4-a2 CH(Me)CH₂ h3 49 3-a2 — h1 [161-164] 50 3-a2 — h2 513-a2 — h3 52 3-a2 CH₂ h1 53 3-a2 CH₂ h2 54 3-a2 CH₂ h3 55 3-a2 CH₂CH₂ h156 3-a2 CH₂CH₂ h2 57 3-a2 CH₂CH₂ h3 58 3-a2 CH(Me)CH₂ h1 59 3-a2CH(Me)CH₂ h2 60 3-a2 CH(Me)CH₂ h3 61 2-a2 — h1 62 2-a2 — h2 63 2-a2 — h364 2-a2 CH₂ h1 65 2-a2 CH₂ h2 66 2-a2 CH₂ h3 67 2-a2 CH₂CH₂ h1 68 2-a2CH₂CH₂ h2 69 2-a2 CH₂CH₂ h3 70 2-a2 CH(Me)CH₂ h1 71 2-a2 CH(Me)CH₂ h2 722-a2 CH(Me)CH₂ h3 73 4-a4 — h1 [48-51] 74 4-a5 — h2 [83-84] 75 4-a3 — h1[228] dec. *1 76 4-a4 — h1 [48-51] 77 4-a7 — h1 [220-224]*1: Shown according to position of substitution on phenyl group*2: decomposition

1H-NMR data (heavy chloroform solvent, internal standard TMS) Units isδ. The number inside the parenthesis indicates the proton ratio. Symbolssignify as follows: s: singlet, d: doublet, t: triplet, q: quartet, m:multiplet, br: broad, brs: broad singlet.

Compound Number 7 in Table 1

1.5 (s, 3H), 2.02 (s, 3H), 2.07 (s, 6H), 2.1-2.3 (m, 2H), 2.5 (t, 2H),3.0 (dd, 2H), 7.2 (s, 1H), 7.25 (s, 1H), 7.27 (s, 1H), 7.3 (d, 2H), 7.6(m, 3H), 7.8 (s, 1H)

EXAMPLE 2 Preparation Production

A preparation containing the compound of the present invention wasproduced according to the method described below.

Oral Preparation (tablets containing 10 mg of active ingredient):Compound of present invention 10 mg Lactose 81.4 mg Cornstarch 20 mgHydroxypropyl cellulose 4 mg Calcium carboxymethyl cellulose 4 mgMagnesium stearate 0.6 mg Total 120 mg

50 g of the compound of the present invention, 407 g of lactose and 100g of cornstarch were uniformly mixed using a fluid bed granulatorcoating device (manufactured by Okawara MFG. CO., LTD.) to obtain thecomposition indicated above. 200 g of 10% aqueous hydroxypropylcellulose solution were then sprayed thereon to produce granules. Afterdrying, the granules were passed through a 20 mesh sieve followed by theaddition of 20 g of calcium carboxymethyl cellulose and 3 g of magnesiumstearate to obtain tablets containing 120 mg per tablet by using arotary tablet making machine (manufactured by Hata Iron Works, Ltd.)with a mortar pestle with a dimension of 7 mm×8.4 R.

EXAMPLE 3

(Antioxidative Action on Lipids In Vitro)

The antioxidative action on lipids in vitro of the compounds accordingto the present invention was evaluated in accordance with the method ofMalvy et al. (Malvy C. et al.,) described in Biochemical and BiophysicalResearch Communications, 1980, vol. 95, pp. 734 to 737,) by measuringthe lipid peroxide activity in a rat brain homogenate. Namely, the ratbrain was removed followed by the addition of five volumes of an aqueoussolution of phosphate buffered saline (pH 7.4) (hereinafter, abbreviatedas PBS) to the brain while cooling with water, homogenizing with aTeflon homogenizer, and centrifuging for 20 minutes at 10,000 g tocollect the supernatant as a brain homogenate. 500 μM cysteine, 5 μMferrous sulfate, and 100 mM KCl were added to the resulting brainhomogenate followed by incubating for 30 minutes at 37° C. and measuringthe malondialdehyde that formed due to decomposition of lipid peroxideusing the thiobarbituric acid method. The 50% inhibitory concentrations(hereinafter, abbreviated as IC₅₀) of the compounds according to thepresent invention were then determined from the measured values. Thoseresults are shown in Table 2. It is apparent that the compoundsaccording to the present invention exhibited antioxidative action onlipids in vitro. TABLE 2 50% inhibitory concentration of anti-lipidperoxide action Compound No. in vitro (IC₅₀, μM)  1 3.3  2 2.9 14 2.5 370.80 49 1.0 Control drug 1 0.23 Control drug 2 0.23

EXAMPLE 4

(Tissue Migration)

Tissue migration of the compounds according to the present invention wasevaluated by measuring the antioxidative action on lipids ex vivo. Atest compound dissolved or suspended in an aqueous physiological salinesolution or aqueous physiological saline solution containing 1%polyethylene hardened castor oil (Nikko Chemicals: Nikkol HCO-60) wasintraperitoneally administered to male SD rats (age: 6 weeks) (purchasedfrom Japan SLC) in groups of 3 animals each at a dose of 100 mg/kg. Theanimals were sacrificed by exsanguination by severing the carotid artery30 minutes after administration followed by removing the brain, heartand kidneys. The lipid peroxide activity of homogenates of each tissuewas measured using the method described in Example 3. The inhibitionrates of the test compounds in each tissue were determined from theamounts of lipid peroxide formed in a control group (physiologicalsaline dose group) and test compound groups. Those results are shown inTable 3. On the basis of these results, the compounds of the presentinvention clearly had a high degree of tissue migration. TABLE 3Inhibition rate of ex vivo anti-lipid peroxide action (%) Compound No.Brain Heart Kidney  1 83 80 87  2 97 69 81 14 84 84 91 37 95 87 89 49 9887 90 Control Drug 1 68 59 75 Control Drug 2 45 57 84

EXAMPLE 5

(Antioxidative Action In Vivo)

The antioxidative action in vivo of the compounds according to thepresent invention was evaluated according to the method described in theJournal of Medical Chemistry (J. Med. Chem., 1997, vol. 40, pp. 559 to573) based on the inhibitory effects on abnormal behavior and mortalityrate following administration of ferrous chloride into the spinalsubarachnoid cavity of mice. Male S1c:ICR mice (age: 5 weeks) (purchasedfrom Japan SLC) were used in groups of 3 to 7 animals each, and wereadministered 5 μl of aqueous physiological saline solution containing 50mM ferrous chloride into the spinal column between the 5th and 6thlumbar vertebra. Symptoms were observed for 20 to 60 minutes followingadministration of ferrous chloride, and scores were determined after 60minutes based on the symptoms shown in Table 4. The test compounds weredissolved or suspended in an aqueous physiological saline solution or anaqueous physiological saline solution containing 1% polyethylenehardened castor oil (manufactured by Nikko Chemicals CO., LTD. under thename of NIKKOL HCO-60), and administered intraperitoneally or orally 30minutes before the administration of ferrous chloride. The 50%inhibitory dose (hereinafter, abbreviated as ID₅₀) of each test compoundwas determined from the score of a control group (physiological salinetreated group) and the score of each test compound treated group. Thoseresults are shown in Table 5. It is apparent on the basis of theseresults that the compounds according to the present invention had theantioxidative action in vivo. TABLE 4 Score Symptoms 0 Normal 1 Frequentbiting of lower abdomen or end of posterior trunk 2 Observation of atleast one of the following changes: (1) Frequent biting of posteriortrunk while turning around (2) Hypersensitivity and attacking responseto external stimuli (3) Trembling 3 Clonic convulsion 4 Tonic convulsionor paralysis of posterior trunk 5 Death

TABLE 5 Antioxidative action in vivo 50% inhibitory dose (ID₅₀ mg/kg)Intraperitoneal Compound No. administration Oral administration  1 6.89.7  2 14 18 14 17 30 37 12 27 49 14 >30 Control Drug 1 >30 >30 ControlDrug 2 20 53

Compounds described in International Publication No. WO 00/00650 wereused for the control drugs. Control drug 1 is the compound shown below.

Control drug 2 is the compound shown below.

EXAMPLE 6

(Retina Migration)

The retina migration of the compounds according to the present inventionwas evaluated. The test compounds dissolved or suspended in 0.1 Naqueous hydrochloric acid solution or 1% polyethylene hardened castoroil (Nikkol HCO-60) solution were orally administered to male SD rats(age: 6 weeks) in groups of three animals each followed by removing botheyes 30 minutes later and separating the retinas while cooling with ice.The retinas were homogenized with a Polytron Microhomogenizer (NS-310E:manufactured by Niti-On Medical and Physical Instruments) in 0.1 MTris-HCl buffer (pH 7.4) while cooling with ice to prepare 5%homogenates. The homogenates were then auto-oxidized for 1 hour at 37°C., and the amounts of lipid peroxide that formed were quantified usingthe thiobarbituric acid method (Masugi, et al., Vitamin, 51, 21 to 29,1977). The dose that resulted in 30% inhibition (ID₃₀) was determinedfrom the inhibition rate at each dose level. Those results are shown inTable 6. It is apparent on the basis of these results that the compoundsaccording to the present invention had action that inhibits theformation of lipid peroxides in the retina ex vivo, and exhibited a highdegree of retina migration. TABLE 6 Inhibitory effect on formation oflipid peroxides in retina ex vivo 30% inhibitory concentration CompoundNo. (ID₃₀ mg/kg, oral administration) 1 16 37 5.2

EXAMPLE 7

(Inhibitory Action on 5-Lipoxygenase (5-LO) and 15-Lipoxygenase (15-LO))

5-LO inhibitory activity was measured using a variation of the method ofCarter et al. (Carter G. W. et al., J. Pharmacol. Exp. Ther., 256, 929to 937, 1991). Namely, after pre-incubating (37° C., 15 minutes) inHank's solution human peripheral blood mononuclear cells and a testcompound dissolved in DMSO (final concentration: 1%), 30 μM A23187 wasadded and the resulting solution was additionally incubated (37° C., 30minutes). The resulting leucotriene B4 that formed was quantified byenzyme immunoassay, and the 50% formation inhibitory concentration (μM)of the test compound with respect to 5-LO was calculated from thatvalue. Those results are shown in Table 7.

15-LO inhibitory activity was measured using a variation of the methodof Auerbach et al. (Auerbach B. J. et al., Anal. Biochem., 201, 375 to380, 1992). Namely, after pre-incubating (4° C., 15 minutes) inphosphate buffer (pH 7.4) 15-LO obtained from rabbit reticulocytes and atest compound dissolved in DMSO (final concentration: 1%), 256 μMlinoleic acid was added and the resulting solution was additionallyincubated (4° C., 10 minutes). The resulting 15-HETE that formed wasquantified by spectrophotometry (OD₆₆₀ nm), and the 50% formationinhibitory concentration (μM) of the test compound with respect to 15-LOwas calculated from that value. Those results are shown in Table 7. Itis apparent on the basis of these results that the compound of thepresent invention had inhibitory action on 5-lipoxygenase (5-LO) and15-lipoxygenase (15-LO). TABLE 7 Lipoxygenase inhibitory action 50%inhibitory concentration (IC₅₀ μm) Compound No. 5-LO 15-LO 37 0.23 2.06

INDUSTRIAL APPLICABILITY

The phenylazole compound of the present invention or the pharmaceuticalacceptable salt thereof has antioxidative activity that is effective forthe treatment of arteriosclerosis as well as ischemic organ disorderssuch as myocardial infarction and cerebral stroke, or for the treatmentof diseases caused by oxidative cytotoxicity, is able to effectivelyinhibit retina disorders caused by photooxidation or the like, can beused in the form of a superior antioxidant that contains the phenylazolecompound according to the present invention, and is useful as a drug forinhibiting oxidative disorders of the retina that demonstrates fewadverse side effects.

1. A compound represented by formula (1): (wherein, R1 represents ahydrogen atom or a C₁₋₆ alkyl group which may be substituted, Arepresents an imidazolyl group or a pyrazolyl group represented by thefollowing formulae:

(wherein R2 and R3 represent a hydrogen atom or a C₁₋₆ alkyl group whichmay be substituted by G1, R4 represents a hydrogen atom or a C₁₋₆ alkylgroup which may be substituted by G1, a C₁₋₆ alkylcarbonyl group whichmay be substituted by G1, or a benzoyl group which may be substituted byG1, n represents 0 or an integer of 1 to 3, p represents 0 or an integerof 1 or 2, and R2 and R3 may be identical to each other, or differentfrom each other, when n and p are 2 or more), B represents a grouprepresented by the following formula:

(wherein R5 and R6 each independently represents a hydrogen atom, acyano group, a hydroxyl group, a halogen atom, a C₁₋₆ alkyl group, aC₁₋₆ alkoxy group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₂₋₆alkenyloxy group, a C₂₋₆ alkynloxy group, a C₁₋₆ acyloxy group, or aC₃₋₆ cycloalkyl group, or a phenyl group which may have a substituent, krepresents 0 or an integer of 1 to 15, and R5 and R6 may be identical toeach other, or different from each other, when k is 2 or more), and Zrepresents a chroman-2-yl group which is substituted by G2, a2,3-dihydrobenzofuran-2-yl group which is substituted by G2, athiochroman-2-yl group which is substituted by G2, a2,3-dihydrobenzothiophene-2-yl group which is substituted by G2, or a1,3-benzoxathiol-2-yl group which is substituted by G2, G1 represents acyano group, a formyl group, a hydroxyl group, an amino group, adimethylamino group, or a halogen atom, G2 is represented by thefollowing formula: NHR (wherein R represents a hydrogen atom, a C₁₋₆alkylcarbonyl group, or a benzoyl group which may have a substituent),or a pharmaceutically acceptable salt thereof.
 2. A compound orpharmaceutically acceptable salt according to claim 1, wherein z is agroup represented by the following formula (A), (B) or (C):

(wherein * represents an asymmetric carbon atom, X1 represents an oxygenatom or a sulfur atom, R7 to R17 each independently represents ahydrogen atom or a C₁₋₆ alkyl group, and G2 is represented by thefollowing formula: NHR (wherein R represents a hydrogen atom, a C₁₋₆alkylcarbonyl group, or a benzoyl group which may have a substituent)).3. A compound or pharmaceutically acceptable salt according to claim 1,wherein A is 1-imidazolyl or 1-H-pyrazole-5-yl which is substituted atthe fourth position on the benzene ring.
 4. A production process of acompound represented by formula (1): (wherein,

R1 represents a hydrogen atom or a C₁₋₆ alkyl group which may besubstituted, A represents an imidazolyl group or a pyrazolyl grouprepresented by the following formulae:

(wherein R2 and R3 represent a hydrogen atom or a C₁₋₆ alkyl group whichmay be substituted by G1, R4 represents a hydrogen atom or a C₁₋₆ alkylgroup which may be substituted by G1, a C₁₋₆ alkylcarbonyl group whichmay be substituted by G1, or a benzoyl group which may be substituted byG1, n represents 0 or an integer of 1 to 3, p represents 0 or an integerof 1 or 2, and R2 and R3 may be identical to each other, or differentfrom each other, when n and p are 2 or more), B represents a grouprepresented by the following formula:

(wherein R5 and R6 each independently represents a hydrogen atom, acyano group, a hydroxyl group, a halogen atom, a C₁₋₆ alkyl group, aC₁₋₆ alkoxy group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₂₋₆alkenyloxy group, a C₂₋₆ alkynloxy group, a C₁₋₆ acyloxy group, or aC₃₋₆ cycloalkyl group, or a phenyl group which may have a substituent, krepresents 0 or an integer of 1 to 15, and R5 and R6 may be identical toeach other, or different from each other, when k is 2 or more), Zrepresents a chroman-2-yl group which is substituted by G2, a2,3-dihydrobenzofuran-2-yl group which is substituted by G2, athiochroman-2-yl group which is substituted by G2, a2,3-dihydrobenzothiophene-2-yl group which is substituted by G2, or a1,3-benzoxathiol-2-yl group which is substituted by G2, G1 represents acyano group, a formyl group, a hydroxyl group, an amino group, adimethylamino group, or a halogen atom, and G2 is represented by thefollowing formula: NHR (wherein R represents a hydrogen atom, a C₁₋₆alkylcarbonyl group, or a benzoyl group which may have a substituent),comprising: a step 1 in which a compound represented by the followingformula (1′)

(wherein R1 represents a hydrogen atom or a C₁₋₆ alkyl group which maybe substituted, A represents an imidazolyl group or a pyrazolyl grouprepresented by the following formulae:

(wherein R2 and R3 represent a hydrogen atom or a C₁₋₆ alkyl group whichmay be substituted by G1, R4 represents a hydrogen atom or a C₁₋₆ alkylgroup which may be substituted by G1, a C₁₋₆ alkylcarbonyl group whichmay be substituted by G1, or a benzoyl group which may be substituted byG1, n represents 0 or an integer of 1 to 3, p represents 0 or an integerof 1 or 2, and R2 and R3 may be identical to each other, or differentfrom each other, when n and p are 2 or more)), B represents a grouprepresented by the following formula:

(wherein R5 and R6 each independently represents a hydrogen atom, acyano group, a hydroxyl group, a halogen atom, a C₁₋₆ alkyl group, aC₁₋₆ alkoxy group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₂₋₆alkenyloxy group, a C₂₋₆ alkynloxy group, a C₁₋₆ acyloxy group, or aC₃₋₆ cycloalkyl group, or a phenyl group which may have a substituent, krepresents 0 or an integer of 1 to 15, and R5 and R6 may be identical toeach other, or different from each other, when k is 2 or more), and Z′is represented by the following formula (A)′, (B)′, or (C)′:

(wherein * represents an asymmetric carbon atom, X1 represents an oxygenatom or a sulfur atom, R7 to R17 each independently represents ahydrogen atom or a C₁₋₆ alkyl group, and G2 is represented by thefollowing formula: NHR (wherein R represents a hydrogen atom, a C₁₋₆alkylcarbonyl group, or a benzoyl group which may have a substituent))is produced by reacting an amine compound represented by formula (2):

(wherein R1 represents a hydrogen atom or a C₁₋₆ alkyl group which maybe substituted, and A represents an imidazolyl group or a pyrazolylgroup represented by the following formulae:

(wherein R2 and R3 represent a hydrogen atom or a C₁₋₆ alkyl group whichmay be substituted by G1, R4 represents a hydrogen atom or a C₁₋₆ alkylgroup which may be substituted by G1, a C₁₋₆ alkylcarbonyl group whichmay be substituted by G1, or a benzoyl group which may be substituted byG1, n represents 0 or an integer of 1 to 3, p represents 0 or an integerof 1 or 2, and R2 and R3 may be identical to each other, or differentfrom each other, when n and p are 2 or more)) with a compoundrepresented by the following formula (3):YOC-B-Z′  (3) (wherein Y represents a hydroxyl group or a halogen atom,B represents a group represented by the following formula:

(wherein R5 and R6 each independently represents a hydrogen atom, acyano group, a hydroxyl group, a halogen atom, a C₁₋₆ alkyl group, aC₁₋₆ alkoxy group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₂₋₆alkenyloxy group, a C₂₋₆ alkynloxy group, a C₁₋₆ acyloxy group, or aC₃₋₆ cycloalkyl group, or a phenyl group which may have a substituent, krepresents 0 or an integer of 1 to 15, and R5 and R6 may be identical toeach other, or different from each other, when k is 2 or more) and Z′ isrepresented by the following formula (A)′, (B)′, or (C)′:

(wherein * represents an asymmetric carbon atom, X1 represents an oxygenatom or a sulfur atom, R7 to R17 each independently represents ahydrogen atom or a C₁₋₆ alkyl group, and G2 is represented by thefollowing formula: NHR (wherein R represents a hydrogen atom, a C₁₋₆alkylcarbonyl group, or a benzoyl group which may have a substituent));and a step 2 in which the nitro compound produced in the step 1 isconverted to an amino group using a reducing agent.
 5. An antioxidantcomprising as its active ingredient at least one compound represented byformula (1):

(wherein R1 represents a hydrogen atom or a C₁₋₆ alkyl group which maybe substituted, A represents an imidazolyl group or a pyrazolyl grouprepresented by the following formulae:

(wherein R2 and R3 represent a hydrogen atom or a C₁₋₆ alkyl group whichmay be substituted by G1, R4 represents a hydrogen atom or a C₁₋₆ alkylgroup which may be substituted by G1, a C₁₋₆ alkylcarbonyl group whichmay be substituted by G1, or a benzoyl group which may be substituted byG1, n represents 0 or an integer of 1 to 3, p represents 0 or an integerof 1 or 2, and R2 and R3 may be identical to each other, or differentfrom each other, when n and p are 2 or more)), B represents a grouprepresented by the following formula: (wherein

R5 and R6 each independently represents a hydrogen atom, a cyano group,a hydroxyl group, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkoxygroup, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₂₋₆ alkenyloxygroup, a C₂₋₆ alkynloxy group, a C₁₋₆ acyloxy group, or a C₃₋₆cycloalkyl group, or a phenyl group which may have a substituent, krepresents 0 or an integer of 1 to 15, and R5 and R6 may be identical toeach other, or different from each other, when k is 2 or more), Zrepresents a chroman-2-yl group which is substituted by G2, a2,3-dihydrobenzofuran-2-yl group which is substituted by G2, athiochroman-2-yl group which is substituted by G2, a2,3-dihydrobenzothiophene-2-yl group which is substituted by G2, or a1,3-benzoxathiol-2-yl group which is substituted by G2, G1 represents acyano group, a formyl group, a hydroxyl group, an amino group, adimethylamino group, or a halogen atom, and G2 is represented by thefollowing formula: NHR (wherein R represents a hydrogen atom, a C₁₋₆alkylcarbonyl group, or a benzoyl group which may have a substituent) ora pharmaceutically acceptable salt thereof.
 6. An antioxidant accordingto claim 5, wherein in formula (1) z is represented by the followingformula (A), (B), or (C):

(wherein * represents an asymmetric carbon atom, X1 represents an oxygenatom or a sulfur atom, R7 to R17 each independently represents ahydrogen atom or a C₁₋₆ alkyl group, and G2 is represented by thefollowing formula: NHR (wherein R represents a hydrogen atom, a C₁₋₆alkylcarbonyl group, or a benzoyl group which may have a substituent)).7. A kidney disease, cerebrovascular or cardiovascular disease treatmentagent characterized by comprising the antioxidant according to claim 6.8. A cerebral infarction treatment agent characterized by comprising theantioxidant according to claim
 6. 9. A retinal oxidation disorderinhibitor characterized by comprising the antioxidant according to claim6.
 10. A retinal oxidation disorder inhibitor according to claim 9 forage-related macular degeneration or diabetic retinopathy.
 11. Alipoxygenase inhibitor characterized by comprising the antioxidantaccording to claim
 6. 12. A 20-hydroxyeicosatetraenoic acid (20-HETE)synthase inhibitor characterized by comprising the antioxidant accordingto claim
 6. 13. A compound or pharmaceutically acceptable salt accordingto claim 2, wherein A is 1-imidazolyl or 1-H-pyrazole-5-yl which issubstituted at the fourth position on the benzene ring.